The increased incidence of obesity with its complications - such as insulin resistance, type 2 diabetes, cardiovascular disease, liver steatosis or cancer - poses one of the predominant health threats worldwide. The increased diet induced adiposity is mainly due to hepatic de novo lipogenesis followed by very low-density lipoprotein (VLDL)-mediated transport of the triglycerides to white adipose tissue (WAT) for storage. Stearoyl-CoA desaturase (SCD) is a critical regulator of lipogenesis and catalyzes the synthesis of monounsaturated fatty acids (MUFA), mainly oleoyl- (18:1n9) and palmitoleoyl-CoA (16:1n7), from saturated fatty acids (SFA), stearoyl-CoA (18:0) and palmitoyl-CoA (16:0), respectively. Variations in 18:1n9 levels in many metabolic diseases indicate a prominent role of SCD in health and disease. We have shown in several studies that the global and skin-specific SCD1 deficiency increased energy expenditure and protected mice against high fat and high carbohydrate diet-induced adiposity, hepatic steatosis and hyperglycemia but the mechanisms of how SCD1 deficiency can result in such protective and beneficial phenotypes has eluded us for some. Using a liver specific SCD1 knockout (LKO) mouse model fed a high carbohydrate diet (HCD), we now show that hepatic SCD1 deficiency enhances tissue glucose uptake and is correlated with dramatic increases in the expression and plasma levels of the fibroblast growth factor 21 (FGF21), a liver derived insulin-sensitizing hormone and adiponectin an adipocyte derived adipokine that are known to regulate whole body lipid and glucose homeostasis. Feeding both male and female LKO mice with triolein, but not tristearin, supplemented HCD reduced FGF21 expression and restored plasma glucose levels. Inhibition of SCD activity in primary hepatocytes induced FGF21 expression which was repressed by treatment with oleate but not stearate. Lipogenic gene expression was reduced when the primary hepatocytes were treated with serum isolated from LKO mice previously fed with HCD while in adipocytes Glut-4 and adiponectin gene expression was increased. We hypothesize that hepatic oleate regulates systemic glucose and lipid metabolism either directly or through the modulation of FGF21 and adiponectin expression. We propose two specific aims. In aim 1, we will define the role of SCD1 deficiency in regulating FGF21 expression in the liver. In aim 2, we will determine whether SCD1 deficiency mediated decrease in hepatic de novo fatty acid synthesis, steatosis, gluconeogenesis, and adiposity is dependent on FGF21 stimulated adiponectin-mediated liver-adipose tissue axis. Establishment of FGF21 and adiponectin as major mediators of systemic metabolic benefits of SCD1 deficiency is significant because SCD1 itself, FGF21 and adiponectin are attractive drug targets for the treatment of human obesity, diabetes and other metabolic diseases.